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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2895-2903.
Prepublished online as a Blood First Edition Paper on December 20, 2005; DOI 10.1182/blood-2005-06-2269.
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Submitted June 7, 2005
Accepted November 15, 2005
Apoptosis and complement mediated lysis of myeloma cells by polyclonal rabbit anti-thymocyte globulin
Martin S Zand*, Thuong Vo, Tina Pellegrin, Raymond Felgar, Jane L Liesveld, J J Ifthikharuddin, Camille N Abboud, Ignacio Sanz, and Jennifer Huggins
Division of Nephrology, University of Rochester Medical Center, Rochester, NY, USA
Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA
Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
Hematology and Oncology Unit, University of Rochester Medical Center, Rochester, NY, USA
Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA
* Corresponding author; email: Martin_Zand{at}URMC.Rochester.edu.
Current monoclonal antibody therapies for multiple myeloma have had limited success, perhaps due to narrow target specificity. We have previously described the ability of polyclonal rabbit anti-thymocyte globulin (rATG) to induce caspase and cathepsin mediated apoptosis in human B and plasma cells. We now extend this observation to myeloma cells. Complement in-dependent cell death was measured after addition of rATG (0.1- 1000 µg/ml) to cultures of mye-loma cell lines or primary CD138+ isolates from patient bone marrow aspirates. rATG induced significant levels of apoptosis in myeloma cell as assayed by caspase induction, Annexin-V bind-ing, subdiploid DNA fragmentation, plasma membrane permeability, and loss of mitochondrial membrane potential. Addition of complement greatly augmented myeloma cell death. Binding of rATG to individual myeloma cell surface proteins, primarily CD38, CD52, CD126 and CD138 was demonstrated by competitive inhibition experiments with targeted monoclonal anti-bodies. Three pathways of cell death were identified involving caspase activation, cathepsin D, and the genistein sensitive tyrosine kinase pathway. F(ab)2 fragments of rATG had reduced pro-apoptotic activity, which was restored by Fc fragments, anti-CD32 or anti-CD64 antibodies. We conclude that rATG is effective agent for in vitro induction of apoptosis in multiple myeloma, and that exploratory clinical trials may be warranted.
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